We then focus on the causative functions of AGEs that impact various aging-related diseases. We also highlight the biological connection of AGE-alcohol-adduct formations to alcohol-mediated tissue injury. Finally, we describe the potential translational research opportunities for treatment of various AGE- and/or alcohol-related adduct-associated disorders according to the mechanistic insights presented.Multiparametric MRI is highly sensitive for detection of clinically significant prostate cancer, but has a 10-20% false negative rate. It is unknown if there are clinical factors that predict MRI invisibility. We sought to identify predictors of MRI-invisible (MRI(-)) disease.
Men undergoing MRI/US-fusion targeted?+?systematic biopsy by two surgeons at our institution from 2015 to 2018 were reviewed. Patient demographics, clinical data, MRI metrics, and biopsy pathology results were obtained by chart review. An MRI(-) tumor was defined as a positive systematic biopsy in a zone without an MRI lesion. Factors associated with presence of MRI(-) tumors were identified using stepwise multivariable logistic regression.
Of 194 men included in the analysis, 79 (41%) and 25 (13%) men had GG1+ and GG2+ MRI(-) tumors, respectively. On multivariable analysis, only Black race was associated with presence of GG1+ MRI(-) tumors (OR 2.2, 95% CI 1.02-4.96). Black race (OR 3.5, 95% CI 1.24-9.87) and higher PSA density (OR 2.0, 95% CI 1.34-3.20) were associated with presence of GG2+ MRI(-) tumors. In non-Black and Black men, detection of MRI(-) tumors on systematic biopsy upgraded patients from no disease to GG2+ disease 1% and 11% of the time, respectively, and from GG1 to GG2+ disease 42% and 60% of the time, respectively.
Black race and PSA density were associated with presence of MRI(-) prostate cancer. Further study on racial differences is warranted based on these results. Surgeons should consider pre-biopsy risk factors before deciding to omit systematic prostate biopsy regardless of mpMRI results.
Black race and PSA density were associated with presence of MRI(-) prostate cancer. Further study on racial differences is warranted based on these results. Surgeons should consider pre-biopsy risk factors before deciding to omit systematic prostate biopsy regardless of mpMRI results.Molecular profiling of cancer is increasingly common as part of routine care in oncology, and germline and somatic profiling may provide insights and actionable targets for men with metastatic prostate cancer. However, all reported cases are of deidentified individuals without full medical and genomic data available in the public domain.
We present a case of whole-genome tumor and germline sequencing in a patient with advanced prostate cancer, who has agreed to make his genomic and clinical data publicly available.
We describe an 84-year-old Caucasian male with a Gleason 10 oligometastastic hormone-sensitive prostate cancer. Whole-genome sequencing provided insights into his tumor's underlying mutational processes and the development of an SPOP mutation. It also revealed an androgen-receptor dependency of his cancer which was reflected in his durable response to radiation and hormonal therapy. Potentially actionable genomic lesions in the tumor were identified through a personalized medicine approach foo his combined modality treatment. This identifiable case potentially helps overcome barriers to clinical and genomic data sharing.Androgen deprivation therapy (ADT) remains the leading systemic therapy for locally advanced and metastatic prostate cancers (PCa). While a majority of PCa patients initially respond to ADT, the durability of response is variable and most patients will eventually develop incurable castration-resistant prostate cancer (CRPC). Our research objective is to identify potential early driver genes responsible for CRPC development.
We have developed a unique panel of hormone-naïve PCa (HNPC) patient-derived xenograft (PDX) models at the Living Tumor Laboratory. The PDXs provide a unique platform for driver gene discovery as they allow for the analysis of differentially expressed genes via transcriptomic profiling at various time points after mouse host castration. In the present study, we focused on genes with expression changes shortly after castration but before CRPC has fully developed. These are likely to be potential early drivers of CRPC development. https://www.selleckchem.com/products/epertinib-hydrochloride.html Such genes were further validated for their clinical relevance using data from PCa patient databases. ZRSR2 was identified as a top gene candidate and selected for further functional studies.
ZRSR2 is significantly upregulated in our PDX models during the early phases of CRPC development after mouse host castration and remains consistently high in fully developed CRPC PDX models. Moreover, high ZRSR2 expression is also observed in clinical CRPC samples. Importantly, elevated ZRSR2 in PCa samples is correlated with poor patient treatment outcomes. ZRSR2 knockdown reduced PCa cell proliferation and delayed cell cycle progression at least partially through inhibition of the Cyclin D1 (CCND1) pathway.
Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.
Using our unique HNPC PDX models that develop into CRPC after host castration, we identified ZRSR2 as a potential early driver of CRPC development.Many systemic therapies for advanced prostate cancer work by disrupting androgen receptor signaling. Androgen indifferent prostate cancer (AIPC) variants, including aggressive variant prostate cancer (AVPC), neuroendocrine prostate cancer (NEPC), and double-negative prostate cancer (DNPC), are increasingly common and often overlapping resistance phenotypes following treatment with androgen receptor signaling inhibitors in men with metastatic castration-resistant prostate cancer and are associated with poor outcomes. Understanding the underlying biology and identifying effective therapies for AIPC is paramount for improving survival for men with prostate cancer.
In this review, we summarize the current knowledge on AIPC variants, including our current understanding of the clinical, morphologic, and molecular features as well as current therapeutic approaches. We also explore emerging therapies and biomarkers aimed at improving outcomes for men with AIPC.
Establishing consensus definitions, developing novel biomarkers for early and accurate detection, further characterization of molecular drivers of each phenotype, and developing effective therapies will be critical to improving outcomes for men with AIPC.